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Metastatic malignancy represents a common cause of effusions. Immunocytochemistry (ICC) is useful in confirming malignancy and gaining insight into the site of origin. Cell blocks are commonly utilized for this purpose; nonetheless, when the malignant cells are sparse, they may not be represented in cell blocks thereby precluding immunophenotypic characterization. Thus, we sought to investigate the utility of direct smear preparations as a platform for ICC in the diagnosis of effusions. Air-dried, unstained direct smears were prepared from 49 malignant effusions and 17 reactive effusions for comparison. ICC for EMA and MOC-31 highlighted the tumor cells in 91 and 98% of the malignant effusions tested, respectively. EMA immunoreactivity was focally observed within the calretinin-positive mesothelial cell population in 1 (6%) of the 17 reactive effusions. ICC for MOC-31 was negative in all reactive effusions. Site-specific immunomarkers were also evaluated. Immunoreactivity for Napsin-A and TTF-1 were observed in 78 and 67% of metastatic lung adenocarcinomas, respectively. ICC for PAX8 highlighted metastatic Müllerian and thyroid carcinomas in 100% of cases tested. CDX-2 immunoreactivity was observed in 25, 60, and 100% of metastatic gastric, pancreatic, and colorectal adenocarcinomas, respectively. Positivity for p63 was observed in 75% of metastatic urothelial cell carcinomas and the one case of pulmonary squamous cell carcinoma examined. Calretinin ICC highlighted the tumor cells in both malignant mesothelioma cases tested as well as the benign mesothelial cells in the reactive effusions. In conclusion, direct smears represent an effective platform for the performance of ICC in the diagnosis of malignant effusions.